Abstract Background: The food and beverage industries continue to challenge study results that show added sugar (AS) promoting obesity risk, despite growing evidence that both AS and artificial sweetener (ArtSw) alternatives have health consequences. The number of Americans consuming foods and beverages sweetened with AS or ArtSw has increased over 30 years?corresponding to the marked rise in obesity over this period. In addition to weight gain, sugar sweetened and ArtSw beverage intakes have been found to increase risk of cardiovascular disease, metabolic syndrome, and type 2 diabetes. Critically, weight gain alone does not account for the increases in chronic illness associated with AS and ArtSw products and may depend on pathogenic fat storage in visceral adipose tissue (VAT), pericardial adipose tissue (PAT) and/or hepatic adipose tissue (HAT). This proposal aims to determine the extent that AS and ArtSw consumables associate with regional and ectopic adiposity and glucose intolerance within the context of usual dietary intake. Objective: In the Coronary Artery Risk Development in Young Adults (CARDIA) study, we will examine the relations of sweeteners (AS and ArtSw), sugar sweetened beverages (SSB), and ArtSw (diet) beverages with the 5 regions of adipose tissues: VAT, PAT, HAT, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) measured at year 25 (Y25) and 10-year change in PAT within the context of usual dietary intake. Further, relations of sweeteners with glucose intolerance will be studied. Methods: Dietary intake was assessed 3 times over 20 years using the CARDIA Diet History. PAT was measured by computed tomography (CT) twice (Y15 and Y25) to examine 10-year change in PAT; and VAT, SAT, HAT, and IMAT were measured at Y25. Oral glucose tolerance was tested 3 times over 15 years and diabetes at every exam. Linear regression will be used to predict the relations of cumulative dietary intake of sweeteners, SSB, and diet beverages with the 5 regional adiposity tissues. Proportional hazards regression will evaluate the relations of sweeteners/beverages with incident glucose tolerance. All models will be adjusted for confounding factors. To examine the sweetener-fat relations within the context of usual dietary intake, effect modification of a western diet pattern will be tested. Effect modification for each of BMI, sex, and race will also be tested. Expectation: We expect positive associations with AS and ArtSw, relatively stronger for the organ- related fat measures VAT, PAT, HAT, and IMAT and glucose intolerance than for the non-organ-related SAT, independent of overall level of obesity as represented by BMI. We further expect that consumers of AS, SSB, ArtSw and diet beverages who also consume a western diet pattern will have the highest risk of adiposity compared to non-consumers of a western diet and sweeteners or beverages. Our findings will provide more evidence that food manufacturers should change the formulation of their products by limiting or changing the type and/or amount of added sweeteners, thereby reducing the potential for some metabolic conditions.